The immune-inflammatory response of oligodendrocytes in a murine model of preterm white matter injury: the role of TLR3 activation

Cell Death Dis. 2021 Feb 8;12(2):166. doi: 10.1038/s41419-021-03446-9.


A leading cause of preterm birth is the exposure to systemic inflammation (maternal/fetal infection), which leads to neuroinflammation and white matter injury (WMI). A wide range of cytokines and chemokines are expressed and upregulated in oligodendrocytes (OLs) in response to inflammation and numerous reports show that OLs express several receptors for immune related molecules, which enable them to sense inflammation and to react. However, the role of OL immune response in WMI is unclear. Here, we focus our study on toll-like receptor-3 (TLR3) that is activated by double-strand RNA (dsRNA) and promotes neuroinflammation. Despite its importance, its expression and role in OLs remain unclear. We used an in vivo mouse model, which mimics inflammation-mediated WMI of preterm born infants consisting of intraperitoneal injection of IL-1β from P1 to P5. In the IL-1β-treated animals, we observed the upregulation of Tlr3, IL-1β, IFN-β, Ccl2, and Cxcl10 in both PDGFRα+ and O4+ sorted cells. This upregulation was higher in O4+ immature OLs (immOLs) as compared to PDGFRα+ OL precursor cells (OPCs), suggesting a different sensitivity to neuroinflammation. These observations were confirmed in OL primary cultures: cells treated with TLR3 agonist Poly(I:C) during differentiation showed a stronger upregulation of Ccl2 and Cxcl10 compared to cells treated during proliferation and led to decreased expression of myelin genes. Finally, OLs were able to modulate microglia phenotype and function depending on their maturation state as assessed by qPCR using validated markers for immunomodulatory, proinflammatory, and anti-inflammatory phenotypes and by phagocytosis and morphological analysis. These results show that during inflammation the response of OLs can play an autonomous role in blocking their own differentiation: in addition, the immune activation of OLs may play an important role in shaping the response of microglia during inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation* / drug effects
  • Cell Proliferation* / drug effects
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Encephalitis / genetics
  • Encephalitis / immunology
  • Encephalitis / metabolism*
  • Encephalitis / pathology
  • Female
  • Inflammation Mediators / metabolism
  • Leukoencephalopathies / genetics
  • Leukoencephalopathies / immunology
  • Leukoencephalopathies / metabolism*
  • Leukoencephalopathies / pathology
  • Male
  • Mice
  • Microglia / immunology
  • Microglia / metabolism
  • Microglia / pathology
  • Oligodendroglia / drug effects
  • Oligodendroglia / immunology
  • Oligodendroglia / metabolism*
  • Oligodendroglia / pathology
  • Poly I-C / pharmacology
  • Pregnancy
  • Premature Birth
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Signal Transduction
  • Toll-Like Receptor 3 / agonists
  • Toll-Like Receptor 3 / metabolism*
  • White Matter / drug effects
  • White Matter / immunology
  • White Matter / metabolism*
  • White Matter / pathology


  • Cytokines
  • Inflammation Mediators
  • TLR3 protein, mouse
  • Toll-Like Receptor 3
  • Receptor, Platelet-Derived Growth Factor alpha
  • Poly I-C